Cardiovascular disease, together with atherosclerosis, is the first cause of death in the world. A variety of risk factors are known to be associated with the pathogenesis of atherosclerosis and cardiovascular disease. These factors include hypercholesterolemia, hyperlipidemia, hyperglycemia, hypertension, obesity, elevated levels of plasma homocysteine and hemostatic factors, family history, the male gender, stress, smoking, lack of exercise, high-fat diets, infectious agents and aging. People with diabetes usually have more severe debility from atherosclerotic events over time than non-diabetics.
Atherosclerosis is a disease affecting arterial blood vessels, and it involves the hardening (calcification) of arteries and the formation of atheromatous plaques within the arteries. As with other chronic diseases, atherosclerosis is believed to be caused by the accumulation of harmful free radicals and reactive oxygen species in the body. It is associated with systemic immune responses and inflammation. Atherosclerosis causes two main problems, infarction (complete coronary occlusion) and aneurysm (partial coronary occlusion), and it can actually be viewed as a problem of wound healing and chronic inflammation. Atheroslerosis may cause brain strokes, heart attacks and peripheral artery occlusive diseases in the lower extremities.
The pathophysiology of atherosclerosis comprises various important steps, including enhanced endothelial focal adhesiveness, permeability and pro-coagulation (endothelial dysfunction), expression of adhesion molecules, monocyte adhesion and immigration, formation of foam cell and fatty streaks, smooth muscle cell (SMC) migration from the tunica media into the tunica intima, plaque formation and finally, plaque rupture and thrombus formation. A prevalent theme in atherosclerosis is thus the presence of oxidative stress and inflammation, due to the oxidation of LDL.
The oxidation of low-density lipoprotein (LDL) has been accepted as an important initial event in the development of atherosclerosis. Reactive oxygen species can stimulate the oxidation of LDL, and oxidized LDL which is not recognized by the LDL receptor is then taken up by scavenger receptors in macrophages leading to foam cell formation and atheromatous plaques. In addition, macrophages also possess toll-like receptors which bind pathogen-like molecules and initiate a signalling cascade which leads to cell activation. These macrophages produce inflammatory cytokines, chemokines, free radicals, growth-regulating molecules, metalloproteinases and other hydrolytic enzymes. Apoptosis of foam cells, which is influenced by cytokine expression and the macrophage activation state also contributes to the formation of a necrotic core.
Previous studies show that among the genes which have increased expression in the atherosclerotic vessel wall are those involved in inflammation, such as chemokine and chemokine receptors, interleukin and interleukin receptors, major histocompatibility complex (MHC) molecules, endothelial cell adhesion molecules, extracellular matrix and matrix remodeling proteins, matrix metalloproteinase genes, transcription factors, lipid metabolism and vascular calcification genes, as well as macrophages and smooth muscle cell specific genes. On the other hand, among the genes with decreased expression in the atherosclerotic vessel wall include anti-adhesive, anti-proliferative and anti-inflammatory genes as well as differentiated muscle markers.
Besides surgical interventions such as angioplasty and bypass surgery, various pharmacological interventions have been used for the treatment of atherosclerosis and the associated cardiovascular disease. Medications to lower cholesterol and LDL as well as those which increase high-density lipoprotein (HDL) are normally utilized to prevent the occurrence of atherosclerosis. For example, statins are used to inhibit an enzyme called Hmgcr (3-hydroxy-3-methylglutaryl-coenzyme-A reductase), which is involved in cholesterol biosynthesis. Yet another therapeutic strategy in the treatment of atherosclerosis is the use of cell cycle inhibitors which include pharmacological agents, irradiation or gene therapy, as vascular proliferation is central to atherosclerosis.
Immunosuppressive and anti-inflammatory drugs such as cyclosporine which block the activation of T cells may also be used as a therapeutic treatment for atherosclerosis. In addition to its cholesterol-lowering properties, statins also show pleiotropic effects including immunosuppressive properties. Vaccination with oxidized LDL, bacteria containing modified phospholipids or heat shock proteins is also an attractive approach to induce protective immunity against atherosclerosis. Yet other approaches include transfer of anti-inflammatory interleukins and administration of decoys and antibodies directed against pro-inflammatory interleukins.
Most of the current approaches however, aim to treat atherosclerosis rather than to prevent it. With the increase in health awareness among the public, it was realized through epidemiological and experimental studies that diets containing high amount of phytochemicals can also provide protection against free radical-induced diseases such as atherosclerosis and cardiovascular disease, due to their high antioxidant activities. For example, dietary antioxidants such as vitamin E, vitamin C, carotenoids, polyphenols and coenzyme Q10 were found to be able to prevent atherogenesis.
Phenolic antioxidants from soy, pomegranate, ginger and red wine were also found to attenuate atherosclerosis either by LDL-dependent mechanisms such as reducing LDL levels, inhibiting LDL oxidation and increasing the antioxidant status or via other LDL-independent mechanisms. Resveratrol, a phenolic phytoalexin found in red wine, was also suggested to mediate cardioprotection through the preconditioning effect, rather than direct protection. Preconditioning is achieved by subjecting the heart to a therapeutic amount of stress, thereby disturbing normal cardiovascular homeostasis and reestablishing a modified homeostatic condition with increased cardiac defences that can withstand subsequent stress insults. Resveratrol was also found to increase the lifespan and survival of mice on a high-calorie diet. Plant phenolics are thus promising candidates for the prevention of atherosclerosis and related cardiovascular disease.
The oil palm (Elaeis guineensis) contains various phytochemicals which possess significant antioxidant properties such as carotenoids, tocopherols and tocotrienols. The extraction of water-soluble phenolics from the palm oil mill effluent (POME) through a completely solvent-free process recovers another type of antioxidant from the oil palm, designated the Essence of Palm® which contains various phenolic acids and polyphenols. This discovery potentiates the two-pronged approach of reducing environment pollution caused by POME while producing premium products for the pharmaceutical, nutraceutical and cosmeceutical markets. Oil palm phenolics showed significant biological activities against LDL oxidation, increased the amounts of HDL in hamsters fed an atherogenic diet and attenuated atherosclerosis in blood vessels of atherogenic diet-fed rabbits.
In this study, we extended the knowledge that oil palm phenolics can attenuate atherosclerosis by hypothesizing that the extract might influence certain gene expression changes. We thus tested this hypothesis by feeding mice with either a low-fat normal diet (14.6% kcal/kcal energy) or a high-fat (40.5% kcal/kcal energy) atherogenic diet containing cholesterol (0.15% w/w). Each group was further given either distilled water (control group) or oil palm phenolics (treatment group). By harvesting major organs such as livers, spleens and hearts for microarray gene expression profiling analysis, we identified the biological changes caused by oil palm phenolics in the normal diet fed mice, by the atherogenic diet and by oil palm phenolics in the atherogenic diet fed mice, as well as discovered how the extract changed the gene expression profiles caused by the atherogenic diet.